The present invention relates to a novel random copolymer, a production method thereof and a medical material. In particular, the present invention relates to a random copolymer that includes both amino groups and phosphorylcholine-like groups and shows biocompatibility as well as excellent physical properties such as wear-resistance. The present invention further relates to production methods of such random copolymers, and medical materials using such copolymers.
Polymers made of 2-methacryloyloxyethylphosphorylcholine (abbreviated hereinafter as MPC, while the polymers are abbreviated as MPC polymers) show high biocompatibility since they have chemical structure similar to phospholipids found in living systems. Technologies have been developed for making use of such MPC polymers in medical high molecular material and in cosmetic materials.
MPC copolymers obtained through copolymerization of MPC and a monomer having a hydrophobic group have hitherto been used as biocompatible materials. A substrate having a surface coated with such a copolymer can be used as, e.g., a medical instrument with little problem as long as exposure of the substrate to blood is for a brief period of time. However, long term exposure to blood may result in gradual dissolution of the applied copolymer into blood or falling of the copolymer off the surface of the substrate. This leads to a problem that the blood compatibility of the medical instrument does not last long.
To avoid these problems, a coating agent has been proposed, for example, in Japanese Patent Publication No. JP-A-7-502053, which contains copolymers obtained through polymerization of a monomer composition containing a reactive comonomer, such as an amino group-containing (meth)acrylate or an amino group-containing styrene monomer, and a monomer having a phosphorylcholine-like group (which may be abbreviated hereinafter as a PC group, while the monomer may be abbreviated hereinafter as PC monomer). The purpose of the reactive comonomer is to allow the coating agent to bind to the surface of the substrate through covalent bonds.
However, amino group-containing (meth)acrylates or amino group-containing styrene monomers are generally expensive and are disadvantageous for industrial use.
In methods disclosed in Japanese Patent Publication No. JP-A-7-184989 and in Japanese Patent Publication No. JP-A-7-184990, an MPC copolymer having epoxy groups and another MPC copolymer having hydroxyl, amino, or carboxyl groups are used to promote the binding of the coating to the surface of substrate such as a medical instrument through chemical bonds.
A copolymer having the number average molecular weight of 45000 is disclosed as an example of the amino acid-containing MPC copolymer. A method for producing this copolymer is also disclosed, wherein 6 g (20 mmol) of MPC, 4.95 g (35 mmol) of butyl methacrylate (abbreviated hereinafter as BMA), 0.18 g (3.2 mmol) of allylamine (which may be abbreviated hereinafter as AAM), and 0.04 g of 2,2xe2x80x2-azobisisobutyronitrile (abbreviated hereinafter as AIBN) are dissolved in 28 ml of ethanol and the reaction mixture is placed in a hot bath at 60xc2x0 C. for 24 hours to carry out polymerization.
However, with this method, it is difficult to obtain high-molecular weight copolymers with number average molecular weight of, for example, 50000 or higher. In addition, the resulting copolymer has limited proportion of amino group content. Therefore, it is difficult to fix these amino group-containing MPC copolymers to the surface of substrate. This may result in a weak coating. Also, smoothness of the surface of the resulting coating may be lost due to the small molecular weights.
A monomer composition containing AAM as a comonomer such as the above-described monomer composition can hardly undergo radical polymerization, generally resulting in polymers with low degrees of polymerization in low yields. In prior art methods, the polymers with high molecular weights cannot be obtained even if other vinyl monomers that can readily undergo polymerization have been copolymerized with AAM. One reason for this seems to be that an auto-termination reaction occurs when allyl hydrogen atoms react with radicals. The reaction is commonly called as an allyl-type destructive chain transfer and described in many journals and textbooks (see, e.g., C. E. Schildnecht, xe2x80x9cAllyl Compounds and Their Polymersxe2x80x9d, Wiley Interscience, p19-30 (1973), R. C. Laible, Chemi. Rev., 58(5), p807-843 (1958), and Takayuki Otsu xe2x80x9cKaitei Koubunshi Gousei no Kagaku (Chemistry of Macromolecule Synthesis, Revised edition)xe2x80x9d Kagaku-Dojin Publishing Company, Inc., p92-95 (1968 first ed.)).
In comparison, radical homopolymerization of AAM salts can produce high molecular weight products with high yields by making use of an azo-polymerization initiator and employing an aqueous polymerization system (S. Harada, S. Hasegawa, Macromol. Chem., Rapid Commun., 5, 27-31(1984)).
Blood compatibility of charged polymers has long been studied from various aspects. For example, materials having excess positive charge on their surfaces are known to exhibit poor blood compatibility (Akaike et al., Japanese Journal of Polymer Science and Technology, 36, p.217 (1979)). Thus, it is desired that the amount of positively charged monomers be kept small in order to improve blood compatibility. Further, the PC copolymers containing reactive groups lose their smoothness if they contain large amounts of the reactive groups since binding reaction to substrate occurs at many locations and the amount of water contained in the resulting PC copolymer layer is reduced. This makes the polymer improper to be used as the material which are required to have smoothness such as a catheter.
It is an objective of the present invention to provide a random copolymer that has an excellent biocompatibility, can readily be bound to a surface of substrate, can exhibit an excellent surface smoothness when applied as a coating, and is thus suitable for use as a material for various surface treating agents, additives, and medical instruments.
It is another objective of the present invention to provide a material for medical use that has an excellent biocompatibility, can readily be bound to the surface of substrate, and can exhibit an excellent surface smoothness when applied as a coating.
That is, according to the present invention, there is provided a random copolymer which is obtained by polymerization of a monomer composition containing allylamine or a salt thereof and a monomer having a phosphorylcholine-like group, wherein the copolymer includes a constituent unit (A1) derived from allylamine or the salt thereof in an amount of 0.01 to 9 mol % and a constituent unit (A2) derived from the monomer having the phosphorylcholine-like group in an amount of 91 to 99.99 mol %, and wherein the copolymer has a number average molecular weight of 50000 to 5000000.
According to the present invention, there is also provided a random copolymer including a constituent unit (a1) derived from allylamine or a salt thereof and represented by formula (1): 
wherein Z is xe2x80x94NH2 or a salt thereof; and
a constituent unit (a2) derived from a monomer having a phosphorylcholine-like group and represented by formula (2): 
wherein R1, R2 and R3 may or may not be identical to one another and each represents a hydrocarbon group having 1 to 4 carbon atoms, R4 represents a hydrogen atom or a methyl group, R5 represents a divalent hydrocarbon group having 1 to 10 carbon atoms, h is an integer from 0 to 10, and j is an integer from 2 to 4;
wherein the random copolymer contains the constituent unit (a1) derived from allylamine and the salt thereof in an amount of 0.01 to 9 mol % and the constituent unit (a2) derived from the monomer having the phosphorylcholine-like group in an amount of 91 to 99.99 mol %, and wherein the copolymer has a number average molecular weight of 50000 to 5000000.
According to the present invention, there is further provided a method for producing the random copolymer. The method is characterized by allowing a monomer composition containing allylamine or a salt thereof and a monomer having a phosphorylcholine-like group to undergo radical polymerization at a temperature of 5 to 80xc2x0 C. in an aqueous solvent containing 50 wt % or more of water with the help of at least one polymerization initiator selected from azo-polymerization initiators and radical polymerization organic peroxides.
According to the present invention, there is still further provided a medical material containing the above-described random copolymer.